Squamous cell carcinoma of the head and neck (SCCHN) is known to develop through complex genetic and epigenetic alterations in genes that control cell proliferation, cell cycle, and cell survival. One set of genes that shows frequently altered expression are genes for growth factors and their receptors, including Epidermal Growth Factor Receptor (EGFR). G-protein- coupled receptors (GPCRs) have been shown to activate the EGFR in SCCHN, resulting in increased proliferation and invasion. This proposal will address the effect on SCCHN cell growth and survival of GPCR signaling cascades that show a dual mechanism: one that is EGFR-independent, as well as one that is integrated with the EGFR. Our preliminary results suggest that two GPCR systems, prostaglandin E2 (PGE2) and its receptors, and bradykinin (BK) and its receptors, stimulate SCCHN proliferation by this dual mechanism. The overall goal of this proposal is to demonstrate the mechanism and importance of signaling through PGE2 and BK in head and neck cancer proliferation, and develop a rationale for combining inhibitors of these GPCR pathways with EGFR inhibitors for the treatment of SCCHN. The long-term goal is to design a clinical trial combining EGFR inhibitors with inhibitors of PGE2 or BK for head and neck cancer patients.